Non-ablative fractional laser 1940-nm treatment modulates epigenetic signatures associated with skin aging in a split-face investigation.

Skin aging is driven by multiple factors, including cumulative environmental damage and epigenetic dysregulation, yet whether energy-based therapies can durably remodel the cutaneous methylome remains unclear. We conducted a split-face, paired longitudinal study in 22 adults treated three times with a 1940-nm non-ablative fractional laser (NAFL). Epidermal samples were collected by tape-stripping from treated and contralateral control sites at baseline, after the first treatment, and after 1, 3, and 6 months. Enzymatic methyl-sequencing profiled ~ 3.8 million CpGs per sample, alongside clinical endpoints: quantitative VISIA measurements and global aesthetic scores. No significant differentially methylated regions (DMRs) were detected immediately post-treatment; however, 635 DMRs emerged 1 month after the final session, expanded through 3 months, and stabilized by 6 months. These loci were enriched for pathways related to epidermal differentiation, collagen organization, wound response, and stem-cell maintenance, with selective modulation at Polycomb-regulated and WNT-signalling genes. NAFL reversed age-associated methylation trajectories at 83.9% of CpGs showing strong differential signal in both the aging reference and NAFL-treatment. Treatment also induced transient, treatment-specific DMRs linked to immune and stress responses. Epigenetic remodelling paralleled significant clinical improvements, indicating that 1940-nm NAFL induces durable methylation changes at loci implicated in skin aging beyond transient wound-repair responses.